Malaria, caused by Plasmodium parasites, remains an enormous global health problem. The blood-stage of the Plasmodium lifecycle causes malaria related morbidity and mortality and also results in formation of gametocytes that are required for the mosquito vector to transmit disease. Here, we provide data that CD4 T cells in humans exposed to seasonal Plasmodium falciparum infections in Mali, Africa upregulate a surface receptor, PD-1, that is associated with an exhausted phenotype in chronic virus infections. To address the generality and relevance of this finding, we applied a novel surrogate activation marker approach to track the total CD4 and CD8 T cell response in a mouse model of Plasmodium yoelii (Py) chronic blood-stage infection. Strikingly, our results show that Py blood-stage infection results in substantial upregulation of surface inhibitory receptors on responding T cells and that these cells exhibit impaired cytokine production, demonstrating that they have undergone functional exhaustion. Of most relevance, blocking inhibitory receptor interactions in mice with established chronic blood-stage Py infection results in immediate control of parasite replication and accelerated clearance of the parasite. New data show that inhibitory receptor blockade enhances CD4 T cell responses and B cells/antibody responses during blood-stage malaria. These results support our long-term goal to understand how inhibitory receptor blockade impacts host immune responses to control clinical malaria. While development of efficacious vaccines and new anti-malarial drugs that target the parasite remain important approaches, successful completion of our studies may reveal an alternative strategy of manipulating host immunity in an antigen-independent fashion for control of the symptomatic blood-stage of Plasmodium infection. We will address these long-term goals through the following specific aims: Aim 1: Determine the T cell components resulting in accelerated clearance of blood-stage P. yoelii infection during inhibitory receptor blockade. Aim 2: Determine the B cell and antibody components resulting in accelerated clearance of blood-stage P. yoelii infection during inhibitory receptor blockade Aim 3. Determine the cellular and humoral basis whereby inhibitory receptor blockade results in complete clearance of persistent P. chabaudi chabaudi blood-stage infection. Aim 4. Determine if and how inhibitory receptor blockade during chronic blood-stage infection impacts cross- species and cross-stage-specific protective immunity to reinfection. PUBLIC HEALTH RELEVANCE: Plasmodium infections cause 300-500 million cases of malaria each year and have a devastating impact on global human health, with particularly high mortality in children living in sub-Saharan Africa. The lack of vaccines and development of drug resistant parasite strains pose major challenges to prevention of malaria. The goal of the current proposal is to evaluate the potential of T cell inhibitory receptor blockade as an approach to control blood-stage malaria infection that does not rely on vaccination and is not complicated by drug resistant parasites.